In 1930 Houssay and Biasotti demonstrated in dog that removal of the anterior pituitary ameliorates the diabetic symptoms (hyperglycemia, glycosuria, ketonuria) resulting from previous pancreatectomy. Houssay, B. A. et al., Compt. Rend. Soc. Biol. 104:407 (1930). Houssay continued these studies by injecting pituitary extract into the hypophysectomized, pancreatectomized dog and reported that the improvement in the diabetic condition was abolished. Houssay, B. A. et al., N. Enal. J. Med. 214:961 (1936). Houssay speculated that the primary pituitary factor for this anti-insulin-like action was growth hormone (GH). More recently, these studies have been confirmed in normal dogs. Indeed, when GH was administered for 32 to 44 days the treatment caused a profound insulin antagonism that initially resulted in increased insulin secretion accompanied by elevated fasting plasma glucose (increased insulin resistance) with eventual exhaustion of the pancreatic .beta.-cell and development of permanent diabetes. Pierluissi, J. et al., Diabetologia 18: 223 (1980).
Diabetogenic actions of GH have also been reported in human. Several studies have examined insulin sensitivity in acromegalic patients. Glucose utilization and suppression of hepatic glucose production was impaired during euglycemic clamps. Hansen, I. et al., Am. J. Physiol. 250:E269 (1986). Forearm muscle glucose uptake after insulin infusion was also decreased in acromegalics. Galbraith, H. et al., Diabetes 9:459 (1960). Impaired glucose tolerance and hyperinsulinemia were reversed by either pituitary surgery, Levin, S. R. et al., Am. J. Med. 57:526 (1974), or bromocriptine therapy, Feek, C. M. et al., J. Clin. Endocrinol. 22:532 (1981). As in acromegalic patients, GH administration to normal volunteers resulted in impaired suppression of hepatic glucose production, decrease glucose utilization, and insulin resistance. Rizza, R. A. et al., Diabetes 31:663 (1982); Bratusch-Marrain, P. R. et al., J. Clin. Endocrinol. Metab. 55:973 (1982) and Fineberg, S. E. et al., Diabetes 23:499 (1974). Because human GH is now readily available, there is increased potential to use it to treat conditions other than GH-deficient children. Recently, Sharp, Beshyah and Johnston, Sharp, P. S. et al., Bailliere Clin. Endo. 6:819 (1992), have warned that when considering such therapies one also need consider iatrogenic secondary diabetes.
These anti-insulin actions of GH aggravate the metabolic problems of patients with insulin dependent diabetes mellitus (IDDM) or Type I diabetes since GH is elevated in those diabetics. Schaper, N. C. ACTA Endocrinol. (Copenh) 122:7 (1990). Elevated GH in IDDM is thought to play an important role in diabetic complications, especially proliferative retinopathy. Holly, J. M. P. et al., J. Endocr. 118:353 (1988). Thus, GH suppression is a likely strategy to treat IDDM. Shumak, S. T. et al., Clin. Invest. Med, 13:287 (1990); Alzaid, A. A. et al., Diabetes Care 17:531 (1994).
In contrast to IDDM patients with little or no insulin secretion, non-insulin dependent diabetics (NIDDM) that are obese as well as non-diabetic obese individuals have elevated circulating insulin associated with depressed GH values. Meistas, M. T. et al., Metabolism 31:1224, (1982). Because insulin promotes storage of fuel as adipose and glycogen and that GH counters this action, low GH levels observed in obesity contribute further to development of adiposity. Thus, it would be desirable to treat obese individuals with GH or an agent that physiologically elevates GH. However, as described above, GH therapy has been demonstrated to counter insulin actions and therefore is contraindicated for individuals with diabetes or for those who are at risk for diabetes. Never-the-less, there have been several trials to examine GH therapy in obese individuals. Gertner, J. M. Horm. Res. 40:10 (1993). Data is far from convincing that such treatment promotes significant loss of fat tissue and there is no data that examined either insulin secretion or insulin sensitivity.
An alternative therapy to GH is to stimulate endogenous GH release by GH-releasing hormone (GHRH). Indeed, some consider this a more physiological approach. Both GHRH and a combination of GHRH with GH-Releasing peptides (GHRPs) have been tested in obese individuals. These studies demonstrated that the GH response to secretagogue is blunted in obesity. Kopelman, P. G. et al., J. Clin. Endocrinol. 23:87, (1985); Csizmadi, I. et al., Metab. 38:1016, (1989); DeMarinis, L. et al., J. Clin. Endocrinol. Metab. 74:1253, (1992); Cordido, F. et al., J. Clin. Endocrinol. Metab. 76:819 (1992); and Ghigo, E. et al., Horm. Metab. Res. 25:305 (1993). Since the intent of these studies was to test pituitary responsiveness to GH secretagogues in obesity and not to treat the pathophysiologic state, the pituitary challenge was acute and there were no attempts to measure insulin sensitivity or pancreatic insulin reserve.
Chronic combined administration of GHRH and GH-releasing hexapeptide has been studied in obese Zucker rats. Bercu, B. B. et al., Endocrinology 131:2800 (1992). The data indicate that the treated obese rats had similar body composition and plasma insulin values as vehicle treated obese counter parts. Additionally, the treated group appeared to tolerate an interperitoneal glucose injection better than untreated obese animals.
Prior to the present invention, GHRH had not been examined in animal models of NIDDM. Most unexpectedly, when GHRH or a functional analog thereof is administered to a diabetic mammal during the period of insulin resistance but prior to .beta.-cell failure, insulin sensitivity as well as insulin secretion is enhanced. Islet cell failure is spared.
Accordingly, the present invention discloses a new, effective therapy for treating mammals afflicted with Non-insulin Dependent Diabetes (NIDDM) and other insulin resistant states such as those associated with obesity and aging. This therapy is contrary to conventional understanding of the diabetogenic properties of GH.